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WDHD-2015-handbook-final

Heartburn – Underlying Mechanisms
David Armstrong, MA, MB BChir, FRCPC,
FRCP(UK)
Division of Gastroenterology &
Farncombe Family Digestive Health Research
Institute,
McMaster University
Hamilton, Ontario Canada
Heartburn is the cardinal symptom of GERD, particularly in
developed, Western countries (1); however, heartburn is not
synonymous with GERD (2). Heartburn can occur, for a variety of
reasons, in the absence of gastroesophageal reflux (GER) or GERD
and, conversely, GER or GERD may exist in the absence of heartburn
or, indeed, other symptoms.
To understand the mechanisms underlying heartburn, one must
appreciate how the esophagus is exposed to refluxed gastric contents,
how gastric refluxate may cause heartburn and other symptoms
and how other mechanisms may cause reflux-like symptoms.
Gastroesophageal Reflux
In health, the reflux of gastric contents into the esophagus is
prevented or minimized by the anti-reflux barrier which comprises
the combined effects of the lower esophageal sphincter (LES), the
crural diaphragm and the ‘flap valve’ effect of the angle of His at
the gastroesophageal junction (3). It is worth noting that the reflux
of gastric contents into the esophagus is a normal phenomenon in
that esophageal acid exposure, measured 5 cm above the LES, is
considered to be normal if esophageal pH is below 4 for less than
4% (55-60 minutes) of a 24-hour recording (4).
Pathogenesis of Gastroesophageal Reflux
Disruption of the anti-reflux barrier can occur if the neuromuscular
function of the LES is impaired or if the anatomical location of the
LES changes relative to the crural diaphragm. If LES function is
impaired, the sphincter opens inappropriately or fails to close appropriately,
allowing gastric contents to reflux into the esophagus. If the
LES is located proximal to the crural diaphragm, the combined effects
of the LES and the diaphragm are separated and, furthermore, the
musculo-mucosal flap valve at the angle of His is effaced or reduced.
The LES is a ring of smooth muscle that extends 3-4 cm across
the gastro-esophageal junction (GEJ) at the level of the diaphragmatic
hiatus, encircled by the crural diaphragm. The location of
the LES, relative to the diaphragm, is maintained by the phrenoesophageal
ligament which can accommodate positional changes
that occur with swallow-induced esophageal shortening and with
diaphragmatic movements during breathing, coughing and physical
exertion. Disruption of the phreno-esophageal ligament allows
the gastroesophageal junction to move proximally, into the chest,
leading to formation of a hiatus hernia.
Lower esophageal sphincter
The LES is, normally, tonically-contracted with a resting pressure
that is 10-30 mm Hg above intragastric pressure. Basal LES
pressure (LESP) is dependent on both intrinsic, myogenic factors
and extrinsic, neural factors; variations in LESP can be caused by
a variety of factors including food, medications, gastric distension,
raised intra-abdominal pressure and neuro-hormonal factors.
Marked reductions in resting LESP may play a role in GER and
GERD but reflux episodes are rare despite short duration increases
in intra-abdominal pressure if the resting LESP is greater than 10
mm Hg and ‘free reflux’, that occurs in the absence of increased
intragastric pressure, is rare if the resting LESP is greater than 5
mm Hg. The effect of reduced basal LESP is exacerbated if there is
a co-existing hiatus hernia.
Relaxations of the LES occur commonly and appropriately to allow
transit of a swallowed bolus into the stomach; these relaxations
are not, generally, associated with GER. In addition, swallowindependent,
transient LES relaxations (TLESR), occur about 3
to 6 times per hour, triggered by gastric distension; TLESRs are
thought to allow physiological venting or decompression of the
stomach and may be associated with audible belching. TLESRs are
identifiable by esophageal manometry as a rapid decrease in LES
pressure that is not triggered by swallowing; they are mediated
by a vago-vagal reflux starting with activation of proximal gastric
receptors which relay signals, via afferent sensory vagal fibres to the
nucleus tractus solitarius (NTS) and, thence, to the dorsal motor
nucleus (DMN) of the vagus nerve. These areas coordinate activity
of the LES and the crural diaphragm which are innervated by the
vagus and phrenic nerves, via the myenteric plexus of the esophagus
and LES. The modulation of TLESRs is affected by a variety
of neurotransmitters including acetyl choline, CCK, opioids,
cannabinoids, nitric oxide, gamma-aminobutyric acid (GABA)
and glutamate. Especially when accompanied by inhibition of the
crural diaphragm, TLESRs are the major mechanism associated
with episodes of GER although TLESRs occur with comparable
frequency in GERD patients and healthy subjects; this suggests
that other factors, such as the pressure gradient across the LES or
the compliance of the GEJ, are important in permitting the occurrence
of GER. TLESRs terminate with the onset of secondary or,
less commonly, primary esophageal peristalsis.
Crural diaphragm
The esophagus passes from the thorax to the abdomen via the
esophageal hiatus in the diaphragm; the right crus of the diaphragm
encircles the LES and, provided that there is no hiatus
hernia, it contracts at the level of the LES to augment the anti-reflux
barrier during inspiration. In health, the LES is maintained in
position, relative to the diaphragm, by the phreno-esophageal ligament;
disruption of the phreno-esophageal ligament predisposes to
an esophageal hiatus hernia with migration of the LES proximally,
into the thoracic cavity.
Hiatus hernia
The role of the hiatus hernia in facilitating GER has been recognized,
anew, over the last 15-20 years as studies with newer manometric
techniques have demonstrated two contributors to the GEJ
pressure zone: the LES and the crural diaphragm. The contribution
of the crural diaphragm and flap valve to the anti-reflux barrier is
World Digestive Health Day WDHD May 29, 2015 WGO HANDBOOK HEARTBURN: A GLOBAL PERSPECTIVE 9